1. Field of the Invention
This invention relates to discodermolide compounds and methods for their making and use.
2. Description of Related Art
(+)-Discodermolide (hereinafter “discodermolide”) is a polyketide natural product isolated from the marine sponge Discodermia dissoluta (Gunasekera et al., U.S. Pat. No. 4,939,168 (1990) and U.S. Pat. No. 5,840,750 (1998)). It is a potent inhibitor of tumor cell growth, acting via a microtubule stabilization mechanism, and has entered phase I clinical trials as an anti-cancer agent.

The supply of discodermolide from natural sources is meager, because the sponge usually inhabits depths where it is harvestable only by submersible vehicles and produces discodermolide in very low concentrations. It is believed that the actual producing organism is a microbial symbiont inside the sponge and not the sponge itself, but efforts to isolate and culture the symbiont have been unsuccessful. Consequently, the availability of discodermolide for clinical trials and research is dependent on material made by chemical synthesis. To date, at least six different total syntheses of discodermolide have been reported: (1) Smith, III et al., J. Am. Chem. Soc., 117, 12011 (1995); Smith, III et al., Org. Lett., 1, 1823 (1999) (additions and corrections Org. Lett. 2, 1983 (2000)); Smith, III et al., J. Am. Chem. Soc., 112, 8654 (2000); Smith, III et al., Org. Lett. 5 (23), 4405–4408 (2003); (2) Mickel et al., Org. Proc. Res. Dev. 8 (1), 92 (2004); Mickel et al., Org. Proc. Res. Dev. 8 (1), 101(2004); Mickel et al., Org. Proc. Res. Dev. 8 (1), 107 (2004); Mickel et al., Org. Proc. Res. Dev. 8 (1), 113 (2004); Mickel et al., Org. Proc. Res. Dev. 8 (1), 122 (2004); (3) Paterson et al., Angew. Chem. Int. Ed., 39, 377 (2000); Paterson et al., Tetrahedron Lett., 41, 6935 (2000); Paterson et al., J. Am. Chem. Soc., 123, 9535–9544 (2001); Paterson et al., Org. Lett., 5, 35 (2003); (4) Harried et al., J. Org. Chem., 62, 6098 (1997); Harried et al., J. Org. Chem., 68 (17), 6646–6660 (2003); (5) Nerenberg et al., J. Am. Chem. Soc. 115, 12621 (1993); Hung et al., J. Am. Chem. Soc., 118, 11054–11080 (1996); and (6) Marshall et al., J. Org. Chem., 63, 7885 (1998); the disclosures of which are incorporated herein by reference.
A review of the various syntheses has been published: Paterson et al., Eur. J. Org. Chem., 12, 2193 (2003). Additionally, many partial syntheses have been reported for one discodermolide synthon or another.
Besides discodermolide itself, many structurally related compounds (“discodermolide compounds”) are known. Some are less abundant congeners isolated from D. dissoluta. Others are by-products or model compounds from one of the aforementioned syntheses. Yet others are the result of efforts to provide an easier-to-synthesize (i.e., less expensive) discodermolide compound or a discodermolide compound having a better spectrum of properties compared to discodermolide itself (which has been reported to produce certain adverse effects). Disclosures relating to discodermolide compounds include: Smith, III et al., U.S. Pat. No. 5,789,605 (1998); Longley et al., U.S. Pat. No. 5,840,750 (1998); Smith, III et al., U.S. Pat. No. 6,031,133 (2000); Smith, III et al., U.S. Pat. No. 6,096,904 (2000); Gunasekera et al., U.S. Pat. No. 6,127,406 (2000); Smith, III et al., U.S. Pat. No. 6,242,616 B1 (2001); Gunasekera et al., U.S. Pat. No. 6,495,594 B2 (2002); Kinder, Jr., U.S. Pat. No. 6,506,910 B1 (2003); Kinder, Jr. et al., U.S. Pat. No. 6,734,177 B2 (2004); Gunasekera et al., US 2001/0049387 A1 (2001); Smith, III et al., US 2002/0103387 A1 (2002); Kinder, Jr. et al., US 2003/0087934 A1 (2003); Kinder, Jr. et al., US 2003/0153601 A1 (2003); Santi et al., US 2004/0018598 A1 (2004); Smith, III et al., US 2004/0048894 A1 (2004); Koch et al., US 2004/0073049 A1 (2004); Kinder, Jr. et al., WO 02/12220 A2 (2002); Chen et al., WO 03/080567 A2 (2003); Martello et al., Chem. Biol. 8, 843–855 (2001); Gunasekera et al., J. Nat. Prod. 64 (2), 171–174 (2001); Curran et al., Org. Lett. 4 (13), 2233–2235 (2002); Gunasekera et al., J. Nat. Prod. 65 (11), 1643–1648 (2002); Gunasekera et al., J. Nat. Prod. 65 (12), 1830–1837 (2002); Minguez et al., Bioorg. Med. Chem. 11 (15), 3335–3357 (2003); Paterson et al., Tetrahedron Lett., 44 (49), 8877–8882 (2003); and Gunasekera et al., J. Nat. Prod. 67 (5), 749–756 (2004); the disclosures of which are incorporated herein by reference.
However, a discodermolide compound having a balance between the positive attributes of discodermolide but without its negative ones has not yet been developed. The present invention provides new discodermolide analogs having attractive activity profiles.